Adverse reactions to NSAIDS Clinical phenotypes:

the skin as a target organ

Dermatology department, University of Lorraine University hospital of Nancy

Pôle des spécialités médicales, Hôpitaux Brabois 54511- Vandoeuvre les Nancy

France

Pr Annick BARBAUD

No conflict of interest

2013

vaculitis Janeway 2005

MPR

FDE

AGEP

Baboon S or SDRIFE

Bircher AJ, Scherer Hofmeier K. Drug hypersensitivity reactions: Inconsistency in the use of the classification of immediate and nonimmediate reactions. J Allergy Clin Immunol. 2012;129:263-4;

An exact description of the morphology and chronology might better help to establish a pathogenetic hypothesis

Immediate reactions to NSAIDs: urticaria and angioedema

Classification of immediate reactions to NSAIDs

1) NSAID-exacerbated respiratory disease, presently designated as aspirin-exacerbated respiratory disease;

2) NSAID-exacerbated cutaneous disease for urticaria and angioedema in patients with chronic idiopathic urticaria. Analogous to aspirin-exacerbated cutaneous disease, this has been identified as aspirin-exacerbated cutaneous disease;

3) Multiple NSAID–triggered urticaria/angioedema in patients without pre-existing chronic urticaria= cross intolerants;

4) Urticaria and/or angioedema, and anaphylaxis induced by a single NSAID

Sanchez-Borges M. NSAID Med Clin North Am 2010; 94:853–63.

URTICARIA

Rounded or oval, red or whitish or flesh-colored bumps (swellings) on the skin that often are very itchy.

Happenning when mast cells release histamine that causes capillaries to leak fluid, that accumulates in the skin, forming swellings.

Hives vary in size. Individual hives fade quickly, in less than 24 hours; Early sign of a whole-body reaction have to be searched: ◦ swelling of the tongue, lips or face; ◦ wheezing; dizziness; chest tightness; and breathing difficulties. ◦ Anaphylaxis (life-threatening condition).

Blanca-Lopez N Value of the clinical history in the diagnosis of urticaria/angioedema induced by NSAIDs with cross-intolerance. Clin Exp Allergy. 2013;43:85-91.

urticaria/angioedema due to NSAIDs

Purpuric vasculitis

Vascular purpura

3 to 10 days after the beginning of the treatment + erythematous papules

◦ +/- urticarial lesions

◦ +/- ulcerations

◦ +/- haemorrhagic blisters.

Renal dysfunction

Role of circulating immune complexes, complement consumption.

Biopsy sample: leucocytoclastic vasculitis

No test and readministration can be dangereous

HS III

Drug photosensitization

• Sensitization to an UV induced metabolite (not to the native drug)

• Redness and swelling of the exposed skin.

• Photopatch tests ◦ series without any UV

exposure ◦ patch tests with a 5 joule

exposure to UVA • Irradiation at 24 h

A: well tolerated

B: sensitizing photometabolite

With a sensitizing potency

Updated list of drug photosensitizers A.Barbaud, Ph.Tréchot, JC. Béani

Website of the French Society of Dermatology + -

• The photopatch test series (26 molecules) of 19 organic UV absorbers and five topical NSAIDs • Applied to the skin of the back and removed at 24 or 48 h • Then irradiated with 5 Jxcm2 UVA

European Multicentre Photopatch Test Study

{ European Multicentre Photopatch Test Study (EMCPPTS) Taskforce. A European multicentre photopatch test study. Br J Dermatol. 2012;166:1002-9.

•Significant number of positive tests with etofenamate may be due to phototoxicity, rather than PACD •Ketoprofen is a potent photoallergen. With an associated photosensitization to benzophenon-3 and octocrylene

PhotoPatch test + à l’Etofénamate à 24h

Series 2013 for photopatch tests

•20 molecules

•5 drugs (3 NSAIDs)

•And add ‘own’ agents used by the patients

{ Benzydamine : responsible for cheilitis and able de chéilites

and in Spain and Portugal

• Cross reactions with many molecules that have a benzophenone structure:

• Most of the chemical sunscreens

• Tiaprofenic acid

• Fenofibrate

• Co-sensitization with fragrances and octocrylene (M. Avenel-Audran et al. Arch Dermatol 2010)

Serrano G. JAAD 1992, 27: 204-8 Le Coz c. CD 1998, 38: 245-52 Durbize E. CD 2003, 48: 144-9 Matthieu L. CD 2004, 50: 238-41

O

Photosensitization to ketoprofen

Sensitization to Percutalgine® Topical sensitization to salicylated drugs

• Sometimes with purpuric lesions

• Usually due to a sensitization to topical salicylated drugs: salicylamide, glycol salicylate

• No case with a systemic sensitization to aspirin

• No contra-indication to NSAIDs orally administered

Fixed drug eruption

A few hours to 3 days after taking the offending drug

Presents round, sharply circumscribed, edematous patchs with violaceous erythema

Associated with pruritus or burning Vesicles or bullae may develop The lesions heal with residual

hyperpigmentation. Drug rechallenge by oral

provocation leading to recurrence of lesions at the same site or multiple newer sites.

59 French cases, time between drug intake and skin symptoms was, on

average, two days.

Brahimi N. et al. A three-year-analysis of fixed drug eruptions in hospital settings in France. Eur J Dermatol 2010; 20: 461-4

Patch tests in situ in FDE

Patch tests: positive on pigmented lesions in 21/47 patients (40.4%),

1 with cetirizine and 20 with NSAIDs (18+/47)

o 9 PT+ / 27 with nimesulide

o 9 PT + / 23 with piroxicam

◦ 0/8 dus au paracetamol.

Andrade P et al. Contact Dermatitis 2011;65:195-201.

Generalized bullous fixed drug eruption

•13 deaths/58 cases (22%)

• vs (47/ 170; 28%) in SJS/TENS

Lipowicz S, Sekula P, Ingen-Housz-Oro S, Liss Y, Sassolas B, Dunant A, Roujeau JC, Mockenhaupt M.

Br J Dermatol. 2013 ;168:726-32.

Generalized bullous fixed drug eruption; Multifocal FDE

Multifocal FDE is a rare cutaneous disorder characterized by numerous erythematous to violaceous well-demarcated plaques occurring on multiple sites each time the causative or a chemically related drug is taken.

Reported with NSAIDs: ◦ celecoxib (Chugh S. 2013), ◦ flurbiprofen (Balta I. 2013), ◦ etoricoxib (Calistru AM, 2011), ◦ etodolac (Kolka Kalkan I. 2013), ◦ nimesulide (Tognetti L, 2013), ◦ ibuprofen (Koshelev MV. 2012)

Maculopapular rash (= morbilliform exanthema)

Rash characterized by extended erythematous macules (characterized by flat spots) and papules (small bumps)

Occurs 1 to 10 days after starting the causative drug

On re-exposure to the drug, skin lesions appear within a few hours to 3 days.

Prompt cessation of the causative drug results in resolution over 1-2 weeks

In an adult is usually due to a drug, but more likely (88%) to be viral in a child

In 107/612 cases of suspected cutaneous drug reactions, a drug was identified as responsible: 25 were due to NSAIDs.

Heinzerling LM, Tomsitz D, Anliker MD. Is drug allergy less prevalent than previously assumed? A 5-year analysis. Br J Dermatol. 2012;166:107-14.

Acute generalized exanthematous pustulosis (AGEP)

Acute drug-related eruption with numerous small, primarily non-follicular, sterile pustules

Arising within large areas of edematous erythema Usually with high fever

(> 38°C) and high blood neutrophil counts (> 7.0 × 109 L–

1) AGEP resolved rapidly, within 2 weeks, after

prompt withdrawal of the culprit drug

Acute generalized exanthematous pustulosis (AGEP)

Histopathological features Spongiform subcorneal pustules,

marked papillary dermis edema and

perivascular neutrophil and eosinophil infiltrates

Sidoroff A, Dunant A, Viboud C, Halevy S, Bavinck JN, Naldi L, Mockenhaupt M, Fagot JP, Roujeau JC. Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR). Br J Dermatol. 2007;157:989-96.

From a multinational case–control study (EuroSCAR): 97 validated community cases of AGEP and 1009 controls.

Drug patch tests are of value in Acute Generalized

Exanthematous Pustulosis (AGEP)

• 26/45 AGEP (50%) in a French multicenter study Barbaud A.et al. Br J Dermatol 2013 168: 555–562 :

• 8 for pristinamycin, 8 for betalactams,

• 3 for corticosteroids, • 2 for iodinated radiocontrast

media (ICM), 2 for dextropropoxyphene in combination with paracetamol (acetaminophen),

• and 1 each for fluindione, non-fractionated heparin, pseudoephedrine (at 1% in petrolatum), tetrazepam, clindamycin, and varenicline. .

From literature, positive patch tests allylisopropylacetylurea, betalactams, bleomycin, carbimazole, celecoxib, ciprofloxacine, clindamycin, corticosteroids, diltiazem, metamizole, methoxalene, metronidazole, morphine, nimesulide, pseudoephedrine, ranitidine tetrazepam

8

18

Drug reaction with eosinophilia and systemic symptoms (DRESS)

•Within 2 months after starting the responsible medication: MPR, edema •Fever, lymphadenopathy •Liver or kidney dysfunction •Hypereosinophilia •+ virus reactivation HHV6, EBV

Kardaun SH et al and The RegiSCAR study group. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): an original multisystem adverse drug reaction. Results from

the prospective RegiSCAR study. Br J Dermatol. 2013 Jul 16.

117 cases were validated as probable or definite DRESS

46 +/72 patch tests in DRESS (64%): drugs with positive patch tests

Barbaud A et al.and Toxidermie group. Br J Dermatol 2013 168: 555–562

• Anti-infectious drugs including • betalactams (14 cases), vancomycin (4 cases), pristinamycin

(3 cases), quinolones (1 case, with cross reactions between ciprofloxacin, norfloxacin, and pefloxacine), amikacin (1 case), pyrimethamine (1 case), and acyclovir (2 cases),

• Non anti-infectious drugs including • carbamazepine (11positive PTs/13 suspected cases), proton

pump inhibitors (PPIs): 5 cases, fluindione (2 cases), spironolactone (2 cases),

• 1 case each: celecoxib (1 case at 30% in petrolatum), olanzapine, citalopram, clobazam, corticosteroids, diltiazem, heparin, lamotrigine, RCM (iodixanol), and tetrazepam.

• Salazopyrine: 0/5 cases

Stevens Johnson syndrome and Lyell’s syndrom= toxic epidermis necrolysis= TEN

Extensive epidermal loss With mucous membrane erosions Impaired general condition Extensive detachment of epidermis ◦ limited in Stevens Johnson syndrome: < 10%, ◦ “transitional SJS-TEN” 10–30%, ◦ more widespread in TEN: > 30%

Nikolsky’s sign Multi-organ failures High mortality (20–25%),

Wen-Hung Chung and Shuen-Iu Hung. Genetic Markers and Danger Signals in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Allergology International 2010; 59: 325-332.

The key mediator for keratinocyte death in SJS/TENs is Granulysin 15-kDa

Released by cytotoxic T lymphocytes and NK cells.

However, it seems difficult to reproduce these mechanisms by drug PTs

Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, Sidoroff A, Schneck J, Roujeau JC, Flahault A. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008;128:35-44.

SJS/NETs and NSAIDs

379 ‘‘community’’ SCAR cases (i.e., patients who developed the adverse reaction outside the hospital and who were admitted because of

symptoms of SCAR) 1,505 controls were included.

Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, Sidoroff A, Schneck J, Roujeau JC, Flahault A. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008;128:35-44.

379 SCAR cases and 1,505 controls were included.

Causes of SJS/NETS in children. Levi N and Regiscar. Medications as risk factors of Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis. Pediatrics. 2009;123:e297-304.